alpha, beta-(polyhydroxyaryl)-alkanamides and methods for their producton



- tegers n and m'may be 1 and 2. V

Patented Jan. 19, 1954 a (POLYHYDROXYARYII): ALKANAMIDES;

THEIR PRODUCTION Kurt Rorig, Chicago, Ill., assignor to G. D. Searle & '00., Chicago, 111., a corporationoflllinois :l a

No Drawing. Application May AND METHODS FOR Serial No. 2,28 ,999" v -The, present invention relates to a new group oforganic amides and; in particulan'to c e-o (polyhydroxyaryl) alkanamides and V to methods foritheir production. The present application is a 'continuation-in-part of my copending-application, Serial No. 167,265, filed June 9, l950; now

abandoned.

:j-Byathis'invention I have provided new compositions of 'matterwhich may be representedby the following structural formula V "R" ooNm wherein R is a lower alkyl radical, R is a member of; the ;class consisting of hydrogen and lower alkyl :radicals,- and n ariol rrz are integers less than'3. 1

-In-1the foregoing" structural formula the radicalshR andRL- 'may represent such lower alkyl' groups as methyl, ethyl and normal and branched chain propyl, butyl, pentylfa'nd hexyl. The radical R may also be hydrogen, l The in- CHaO . I ciao-Garbo I Alkyl ON are-effective as hormonalagents, These amides have a pronounced effect on'the cardiovascular system; .specificallyt' as antihypertensive 1 agents.

The compounds of this invention have pharmacodynamic properties. Certain of them These amides are also of value as'intermediatesj in chemical synthesis, e; g. of such compounds as 3,4-bis-(p hydroxyphenyl)-2-hexanone and its .ethers,' "which are the subject of my copend- I compound. adds an all;

- 2 ing application of Serial No. 191,493, filed October 21,1950, now abandoned. They can also-be used to produce the N,N-dialkyl and dialkylaminoalkyl derivatives by transamination; a The amides of thisinventionmay be obtained by a number of "methods. nitrile of the type 3 9 N 0 3! described in application Serial 162,603,

filed May 17, 1950,; now;abandoned,. can be hydrogenated, e. g. by hydrogen in presenoe of platinum under pressure,. to producethe alliyl nitrile of the type r a t.

' 01130 N OCH:

This same type of alkyl nitrile is'p'repared in excellent yield by condensing an alkoxybe'nzal-fi dehyde with alkoxybenzylcyanide and" react\ ing the resultant acrylonitrile with an alkyl magnesium halide. The reaction may be described schematio'allyflas follows 7 ciao-@0110 No-cm-Gdbm l C H:

A 57 I v 7? 1 Alkyl on a *is' 'i. ind cated th ias ws id f d itim a-alkyl' deriyatii're."v g Y:

ofnitriles are conyerted into the amides "by, drohalic acid; suchas l iy rob'romic a'cidand' of" polar organic solvent'ih'yrhichall the reactants are soluble, preferably glacial acetic"'*acid;"-with" simultaneous hydrolysis-of' the phenolic ethers to I Thus, an alkenoaccent the free phenols. Etherification is accomplished by the usual methods, such as treatment with a dialkyl sulfate or alkyl halide in alkali. In order to verify the structure of the ethers thus produced, the a, 3-di-(p-anisyl)valeramide was prepared also from the corresponding valeric acid. Mixed melting point tests confirm the identity of the ethers. The ethers are reconverted to the hydroxy compounds by treatment with pyridine hydrochloride or aluminum bromide.

The following examples illustrate in detail certain of the compounds which comprise this invention and methods for producing same. However, this invention is not to be construed as limited in spirit or in scope thereby. It will be apparent to chemists skilled in the art that many modifications in materials and methods may be made without departing from the invention. In each of these examples, uncorrected temperatures are given in degrees centigrade (C.), relative amounts of materials in parts by weight and pressures during vacuum distillations in millimeters (mm.) of mercury.

Example 1 A solution of 100 parts of a,fl-di-(p-anisyl) valeronitrile in 700 parts of hot glacial acetic acid is treated with 570 parts of 48% hydrobromic acid and heated at refluxing temperature for 3 hours.

Almost immediately after starting the reflux period, the solution becomes deep purple-blue. The color changes to reddish-purple after minutes and finally light walnut-brown. The solution is then poured into 6000 parts of ice-cold water. The fine, almost gelatinous, white precipitate is filtered and washed with water. After two recrystallizations from ethyl acetate, the a,,B-bi$ (p-hydroxyphenyl)valeramide melts at about 2'74 to 275 C. It has the structural formula Example 2 Four parts of a,p-di-(p-anisyl)valeric acid are heated at refluxing temperature for 8 minutes with 66 parts of thionyl chloride. The resulting a,p-di-(p-anisyl)valeryi chloride is poured into 178 parts of a concentrated aqueous solutionof. ammonia. The pinkish-white solid is recrystallized from absolute alcohol to give colorless crystals melting at about 277 to 229 C. The same p-di-(p-anisyl)valeramide is obtained from a, 3-bis-(p-hydroxyphenyl)valeramide by treatment with dimethyl sulfate and with diazomethane. Mixtures of crystals obtained by these three methods show no depreciation in melting point.

Example 3 19 parts of a,p-di-(m-anisyl)butyronitrile are dissolved in 140 parts of hot glacial acetic acid and 148 parts of 48% hydrobromic acid are added Example 4 A solution of 23 parts of metallic sodium in 420 Example 5 To a solution of 44 parts of m,p-dimethoxy phenylacetonitrile and 34 parts of p-anisaldehyde in 160 parts of methanol a solution of 13.5 parts of sodium methoxide in 56 parts of methanol is added. The creamy yellow product begins to form at once. After standing for several hours, the a. (m,p dimethoxyphenyl) B (p-anisyl) acrylom'trile is collected on a filter and recrystallized from ethanol in the form of light yellow crystals, which melt at about 131 to 132 C.

A solution of 141 parts of this product in 880 parts of thiophene-free benzene is treated in the course of 10 minutes at 65 C. with a solution of 69.5 parts of ethyl magnesium bromide in 370 parts of ether. A greenish-yellow, viscous 011 forms immediately. The suspension is heated at refluxing temperature for one-half hour, then decomposed by pouring upon ice and dilute sulfuric acid. After thorough stirring the organic layer is dried briefly over anhydrous potassium carbonate and evaporated to yield a brown oil which slowly solidifies on standing. On recrystallization from 95% ethanol a crystalline racemic isomer of a- (m,p-dimethoxyphenyl)-,6-(p-anisyl)valeronitrile is obtained, which melts at about 112.5 to 114.5 C.

The ethanol is removed by evaporation from the mother liquor from which the solid isomer had been obtained. The residual oil is then distilled to give an approximately equal amount of the other racemic isomer of a-(m,p-dimethoxyphenyl) -;8-(p-anisyl)valeronitrile, which boils at 197 to 202 C. at 0.5 mm. pressure. On standing, the oil solidifies to a glassy material.

36 parts of the solid crystalline isomer of a- (m,p dimethoxyphenyl) fi-(p-anisyDvaleronitrile, melting at about 112.5 to 114.5 C., are hydrolyzed for 40 hours by 15 parts of sodium hydroxide in 280 parts of ethylene glycol containing 10% water. Upon acidification of the alkaline solution a brown oil is obtained which solidifies on standing. This is recrystallized from ethanol to give a crystalline racemic isomer of a- (m,p-dimethoxyphenyl) -B- (p-anisyl) valeric acid which melts at about 141 to 142 C.

20 parts of this material are refluxed for 3 minutes with 200 parts of water-White thionyl chloride. The resulting solution is poured cautiously into 440 parts of concentrated aqueous ammonium hydroxide. The tan colored precipitate isfiltered, washed and recrystallized from ethanol to yield White crystals of a-(m,p-dimethoxyphenyl) -;8 (p-anisyl) valeramide, melting at about 1'77 to 178 C. This compound has the structural formula 0 OH: 01115 c ONHz OCH;

50 parts of a-(mp-dimethoxyphenyllrfiripe anisylwaleronitriler are refluxed for '2, hoursin'a solution containing 225 parts ofAB aqueous hyj drobromic acid and 200 parts of glacial acetic acid. The mixture is poured into 3000- parts of cold water whereupon an oilfseparateswhich is extractd'with ether'IThe ethereal solution is exti'o'ri: The alkaline extract a is j ren:

thIlQ OO parts of a 4% aqueous sodium 'y 'jaitld ition for dilute hydrochloric acid and th'e'bilwhich' separates is extracted with ether. The ether extract is dried over anhydrous sodium sulfate, filtered and evaporated. A glasslike orphous solid mixture of the two racemic a. ihydroxyphenyl) ,B'f- (p "lh'yd'roxy-. phe y aleraniides isth'us obtained.

The same compounds are obtained from the a. (m,p-dimethoxyp henyl)' 5 (p anisyl) valeramides, described'in the preceding sample, by refluxing parts of these triethers with 50 parts "of "freshly distilled pyridine hydrochloride for45 minute's; The products'have the structural I formula (EQHE $ONH2 l 7 HooH-cH- OH Example 7 To a. solution of 33 parts of ethyl magnesium bromide in '60rpart s of absolute ether are added portionwise in 30 minutes 76 parts of a,c-di-(panisyDacrylonitrile. After refluxing for 4 hours there are added dropwise in'the course of 5 minutes 80 parts of methyl iodide. The mixture is refluxed for "one hour and then decomposed with ice. and'hydrochloric "acid. The ethereal layer is separated, dried over anhydrous potassium carbonate and distilled to give the mixture of two racemic isomers of a,;8-di-(p-anisyl -a-methylvaleronitrilen', This is a viscous white oil boiling at about 1625165 50, at 0.003 mm. pressure.

er a inixtureof the two race'rnic a,,6-dixm a copperflask 'with'f'3615 partsfof di ene glycol, 16 partsof sodium hydroxide; pel- I and parts of water for 25 hours. i Thehot s ioii is curedinto-loililparts of watergfro w h- ;an"1nisoluble; grey,"semi'- solid materialis o ned by 'decantationofthefliguid. *Theliqdid-ls renderedacidic "by addition'bf dilute hydrochloric acldggnd fljiPlfQQiPitEttBjOi the racemic (p anisyll-a-methylvaleric acids forms. e ,H

above'decantatidn is triturated "with ether" to give a precipitate of the higher melting, solid racemic tural formula is Go on:

Example 8 I 10 parts of a mixture of the two racemic (1,}3-dl- (p-anisyl) -a-methylvaleronitriles, prepared as in C2135 (IJONHQ CH-C Example 7, are refluxed for hours in a solution.

containing 50 parts of glacial acetic acid and 5? parts of a 48% aqueous hydrobromic acid solumethylvaleronitriles is heated under olid. productfremaining after. the I refluxed for BhOursan-dfthen SOIparts' fFjethyIi iodide are added dropwise. Refiuxingis resinnedfor one hour, after which the mixture is poured over ice and hydrochloric acid? The'ether layer of glacial acetic acid and 120 pai'ts' of a" e337, aqueous hydrobromic acid solution are heated at have the structural formula 10. 1.. Thedepenrnur l sql tio s panned into. 5Q parts of water toyield a white, semi solid prod;

uct which is separated and recrystallized from-- Z-nitropropane to yield mainly the higher-melting, ra'cemic a, 8-bis-(p hydroxyphenyl)--a-methylvaleramide, which melts at about225-234" C. The nitropropane mother liquor is evaporated ,to yieldan oil rich. in the lower-melting, racemic afi bis (p hydroxyphenylya --methylva1er-- amide. 1

The-products are likewise obtainable from the ethers described in- Example 7, by refluxing 20 parts of the 6,;3-di-(p-anisyl)-a-methylvaleramides for minutes; with 1( )0 parts of freshly The 1 m distilled pyridine hydrochloride.

, coNHi xam 9 To a solution of 119 partsof methyl magnfir, slum bromide in 640 parts of absolute'ethr afe" addedin the courseof 30 minutes 76 p'arts of a (o-anisyl) -fl- (p-anisyl) acrylonitrile, prepared according to the method of J. B. Niederl and A. Ziering (Journal American Chemical Society, vol. 64:, pages 995 et seq:;"194-2l;'-""The'mixtureffis is separated, dried over anhydrous potassium carbonate, filtered and evaporated. The residue i a viscous oil which consists of the mixture of the two racemic isomers of a-(o-anisyl) -aethyl-fl-(p-anis'yl)butyronitrile. 20 parts of this mixture of isomers, 100 parts refluxing temperature for i hours. The resulting The'products have the structural formul mixture is'pouredinto 1000 parts-of ice'water to yield a whitish precipitate. The supernatant is decantedand the residue dissolved in hot nitropropane. Qn cooling, the higher melting isomer of a (o-hydroxyphenyl) -a ethyl- 8 -(p-hydroxyphenyl)butyramide is obtained. Evaporatio of the'mother liquor yields; the iow r'me H; CONE:

I claim:

the structural formula 1. The amides of R OONH:

wherein R- represents a lower alkyl group. R represents a member of the class consisting of hydrogen and lower alkyl groups, and m is a positive integer less than 3. I

2. The a,c-bis-(hydroxyphenyl)alkanamides of of the structural formula HO R (N111 OH -Q wherein R represents a lower alkyl group.

3. The a,B-bis-(p-hydroxyphenyl) alkanamides of the structural formula com,

wherein R represents a lower alkyl group.

4. The a,B-bis-(hydroxyphenyl) -a-alkylalkanamides of the structural formula H R CONHz wherein R and R represent lower alkyl groups and m is a positive integer less than 3.

5. The afi-bis-(p-hydroxyphenyl) alkanamides of the structural formula R CONE? wherein R and R represent lower alkyl groups.

6. The process of producing an amide of the structural formula HO R CONE:

(OHM

wherein R. represents a lower alkyl group, R represents a member of the class consisting of hydrogen and lower alkyl groups and m is a positive integer smaller than 3, which comprises the heating of a nitrile of the structural formula Alkyl-O R ON (OAlkyl) wherein R and R. and m are defined as hereinabove, with a concentrated aqueous hydrogen halide in strong acetic acid substantially at the boiling point of the mixture.

7. The process of producing an ewis-(hydroxyphenybalkanamide of the structural formula HO R CONHz OH wherein R is a lower alkyl group, which comprises the heating of an a,/3-dianisy1alky1 cyanide of the structural formula r OH3OCaH4CH-CHCeHiOCH with a concentrated. aqueous hydrogen halide in 8 glacial acetic acid at the boiling point of the mixture. 7.

8. The process of producing an a,fi-bis-(phydroxyphenyl) alkanamide of the structural formula R CONH:

wherein R is a lower alkyl group, which comprises the heating of an a,p-di-(p-anisyl)- alkyl cyanide of the structural formula R CN CH3OCuH ]HHCeH40 CH3 with concentrated hydrobromic acid in glacial acetic acid at the boiling point of the mixture.

02H: C ONH:

10. The a, 8-bis-(hydroxypheny1) butyramides. 11. The a-dihydroxyphenyl-fl-hydroxyphenylalkanamides of the structural formula HO 0 ONH2 (OH):

wherein R, represents a lower alkyl group.

OH CzHs 0 ONE! KURT RO-RIG.

C2115 C ONHz References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Migrdichian: The Chemistry of Organic by Cyanogen Compounds, (1947) pp. 37 and 46. 

1. THE AMIDES OF THE STRUCTURAL FORMULA 